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bioRxiv · 10.1101/2025.01.11.632297

Anticancer synthetic arylsulfonamides with Wnt1-modulating activity

Gutti, M.·Luo, J.·Sharma, V.·Lee, E.·Desarkar, A.·Raval, R.·Soedarmono, A.·Zhu, J.·Njoo, E.
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Abstract

Dysregulation of the Wnt1/{beta}-catenin signaling pathway has been demonstrated to be a driving factor in the propagation of several human cancers. Previous studies have discovered methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate (MSAB) as a selective inhibitor of the Wnt1/{beta}-catenin signaling pathway, which putatively functions through direct engagement of {beta}-catenin. To understand how changes to the identity and position of the methyl ester affect the in vitro potency of this compound in Wnt1-driven mammalian cell lines, we prepared and evaluated three analogs of MSAB with 3- and 4-substituted methyl and ethyl esters. In MTT assays, analogs with methyl esters showed significantly more activity than their ethyl ester counterparts and both 4-substituted esters exhibited significantly attenuated antiproliferative activity, with MSAB exhibiting dose-dependent activity across cancerous cell lines. Further analysis by flow cytometry reveals low-Annexin V signal, suggesting that these compounds do not function via a pro-apoptotic pathway. Additionally, through a TCF/LEF-activated luciferase reporter cell assay, we observe that the 4-substituted methyl ester analogous to MSAB exhibits slightly diminished Wnt1-inhibitory activity, while 3- and 4-substituted ethyl esters exhibit minimal Wnt1-inhibitory activity. This difference in potency with a simple ester substitution might be attributed to several factors that ultimately drive antiproliferative activity, prompting the investigation of other potential substituents to further investigate the structure-activity relationship of these compounds as Wnt1-based antiproliferative agents.

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Gutti, M., Luo, J., Sharma, V., Lee, E., Desarkar, A., Raval, R., Soedarmono, A., Zhu, J., Njoo, E.. 2025-01-14. Anticancer synthetic arylsulfonamides with Wnt1-modulating activity. https://doi.org/10.1101/2025.01.11.632297

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